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Abstract

Background and Purpose— Antithrombotic therapy has been demonstrated as an effective tool for secondary ischemic stroke prevention. Nevertheless, scant data are available on actual prescription of this therapy in clinical practice.

Methods— A total of 17 337 patients admitted to geriatric and internal medicine wards participating in the study in the 1993 to 1998 survey period were analyzed. Patients with coded diagnoses of ischemic stroke and transient ischemic attack (TIA) were selected. Data recorded included demographic and clinical characteristics and medication prescription during hospital stay and at discharge. Logistic regression analyses were used to identify conditions associated with the prescription of antiplatelet or anticoagulant drugs.

Conclusions— A high rate of patients affected by stroke or TIA are discharged from the hospital without antithrombotic therapy. The most important correlates of the likelihood of not receiving an antithrombotic medication were cognitive and functional status.

Incidence of stroke increases with age, and 75% of stroke affects the elderly.1,2 Patients recovering from an ischemic stroke or who have had recent transient ischemic attack (TIA) are at high risk for stroke recurrence. Among patients who survive an acute stroke, the risk of recurrent stroke is highest within the first few weeks, ≈10% in the first year and ≈5% per year thereafter.3 Stroke recurrence increases mortality, disability, institutionalization, and may lead to cognitive impairment and dementia.4

Despite recent advances in the treatment of acute ischemic stroke, the number of effective and feasible treatments remains limited.5,6 For this reason, prevention of ischemic stroke, particularly secondary prevention, is a major clinical and public health issue.7 The efficacy of antiplatelet and oral anticoagulant therapy in stroke prevention has been clearly demonstrated by several clinical trials8,9; conversely, few data exist regarding the actual prescription of secondary prevention treatment in clinical practice, and some studies highlighted inadequate management of patients with previous stroke or TIA.10,11

The aim of this study was to describe the prescription of antiplatelet and oral anticoagulant therapy in patients hospitalized for an acute ischemic stroke or TIA. In addition, we sought to identify demographic and clinical factors that may affect this type of prescription at discharge from the hospital.

Materials and Methods

Patients and Setting

The study protocol of the Italian Group of Pharmacoepidemiology in the Elderly (Gruppo Italiano di Farmacoepidemiologia nell’Anziano [GIFA]) study has been described elsewhere.12 Briefly, the GIFA is a multicenter periodical survey of hospitalized older patients. All patients admitted to 81 clinical centers homogeneously distributed throughout Italy were enrolled and followed-up until discharge. The study periods were the following: May 1 to June 30 and September 1 to December 31, 1988; May 15 to June 15, 1991; and May 1 to June 30 and September 1 to October 31 in 1993, 1995, 1997, and 1998. For each participant, a questionnaire was completed at admission and updated daily by a study physician who received specific training. Data recorded included demographic characteristics, medications used before admission and during hospital stay and those prescribed at discharge, possible adverse drug reactions, and admission and discharge diagnoses.

For this project, only patients enrolled during 1993, 1995, 1997, and 1998 surveys were considered. Data collected in 1988 and 1991 were not included because most of the randomized clinical trials showing the protective effect of antithrombotic therapy were published in the 1990s.8 Moreover, according to the anatomical therapeutic chemical classification, acetyl salicylic acid was not classified as an antiplatelet drug until 1993. Therefore, our study population was limited to 17 337 patients enrolled in the 1993 to 1998 period. Of them, 946 who had a main discharge diagnosis of ischemic stroke or TIA represent the final sample.

Prevalent Disease Ascertainments

All diseases diagnosed by the physicians were classified according to the International Classification of Disease, 9th revision (ICD-9). Cases of ischemic stroke and TIA were identified on the basis of the ICD-9 code (434 to 434.9, 436, 433.01, and 435 to 435.9, respectively). In addition, the following diseases were considered: hypertension, atrial fibrillation, diabetes, congestive heart failure, coronary heart disease, peptic ulcer, and gastroduodenitis. Prevalence of anemia was classified according to WHO criteria (male: hemoglobin <13 g/dL; female: <12 g/dL). To estimate the global burden of diseases, an index of comorbidity was calculated using the Charlson index (CI) score, modified by Deyo et al.13 Subjects were classified into 3 comorbidity groups as follows: CI=0; CI=1 to 2; CI>2. Onset of adverse drug reactions related to antiplatelet or anticoagulant medications prescribed during hospitalization were assessed using the Naranjo algorithm.14

Ascertainment of Drug Prescription

All drugs prescribed during hospital stay and at discharge were abstracted from hospital charts and codified according to the anatomical therapeutic chemical classification. Drugs considered for the analysis were the following antiplatelet drugs: acetyl salicylic acid, ticlopidine, indobufen, clopidogrel, dipyridamole, and picotamide; the following anticoagulant drugs were also considered: warfarin and acenocoumarol.

Cognitive and Functional Status

Cognitive and functional status was assessed at the time of admission and at discharge. Cognitive function was assessed using the Hodkinson Mental Test, a 10-item screening test for dementia.15 The presence of cognitive impairment was identified by the presence of ≥4 errors on the test administered at discharge.

Functional status was evaluated using 6 basic activities of daily living, including transferring from bed to chair, walking in a small room, eating, bathing, using the toilet, and personal hygiene procedures. Patients were considered with severe disability if they needed intensive assistance in at least one activities of daily living and were considered with mild–moderate disability if they needed only supervision or limited assistance in at least one activities of daily living at the time of discharge from the hospital.

Statistical Analysis

Descriptive statistic of selected characteristics was presented according to main diagnosis. We used the ANOVA to compare continuous variables and the χ2 test for the comparison of proportions. Factors potentially related to antithrombotic prescription at discharge were compared in patients who had or did not have the prescription, using univariate logistic regression. Because <5% of the subject were using oral anticoagulant therapy, the analysis was performed for antiplatelet and anticoagulant drugs in combination. Multivariate logistic regression analysis was then used to identify factors independently associated with the prescription of antiplatelet or anticoagulant drugs. The selection of the variables to be included in the model was made on the basis of clinical plausibility and according to the result of the unadjusted analysis. The OR with 95% CI was used as measure of the association between demographic and clinical characteristics and the probability of being treated with antithrombotic medication.

Results

Table 1 reports the principle patients characteristics according to the type of diagnosis. As depicted in Figure 1, >40% (N=385) of the patients were discharged without antiplatelet or anticoagulant prescription, 55.1% (N=521) had antiplatelet, and 4.6% (N=43) oral anticoagulant therapy prescription. Patients with stroke were more likely to be untreated compared with patients with TIA (52.1% versus 30.8%). With regard to the survey period, there was an increase in the antithrombotic therapy prescription from 1993 (46.2%) to 1995 (51.8%) and to 1997 (77.9%); however, from 1997 to 1998, the rate of treatment prescription decreased, with the 1998 prescription rate being 69.0%.

Multivariate logistic regression analysis (Table 3) showed that cognitive impairment (OR: 0.58; CI: 0.43 to 0.78) and severe disability (OR: 0.48; CI: 0.31 to 0.76) were inversely associated with the likelihood of treatment prescription. Other conditions significantly associated with the probability of being treated with antithrombotic therapy were diagnosis of TIA, diagnosis of anemia, and adverse drug reactions. Patients with ≥3 risk factors for stroke were also more likely to have the prescription, but the association was non-statistically significant (P=0.106).

Finally, to further explore the relationship of cognitive and functional status and the treatment prescription, we performed a stratified analysis according to physical and cognitive status. This was performed creating 9 mutually exclusive groups according to cognitive and functional performance levels (Figure 2). Patients with dementia or with very low (≤2) Hodkinson Mental Test scores were excluded. After adjustment for age and sex, we found an independent and additive effect of physical and cognitive status on antithrombotic therapy prescription, with patients with both good cognitive and physical function having the highest probability of being treated. Of note, even among subjects with normal cognitive function there was a graded and strong relationship between the level of physical impairment and the likelihood of antithrombotic prescription.

Discussion

We found a considerably high rate of patients with acute ischemic stroke or TIA discharged from the hospital without the prescription of antithrombotic therapy. More than 40% received neither antiplatelet nor anticoagulant agents; in others words, at least 4 out of 10 patients were not managed according to current international recommendations.16 Moreover, we found that among the large number of demographic and clinical variables considered, cognitive and functional status were the conditions more strongly associated with the probability of having antithrombotic prescription.

Previous studies suggested that there is discrepancy between knowledge derived from clinical trial and clinical practice,17 showing that a significant number of patients with previous stroke do not receive adequate medical intervention.18 Two recent studies reported a low rate of antithrombotic treatment, but they were unable to determine whether the observed low rates were the result of hospital’s failure to prescribe preventive treatment or discontinuation of the treatment by family physicians.19,20 Our results are in agreement with these observations and suggest that physicians operating in the acute care setting may, at least partially, be responsible for the low rate of antithrombotic treatment reported in several surveys. The rate of patients without antithrombotic treatment observed in our study was higher (41%) than that reported in the other studies (25% to 28%).19,20 This could be caused by the specific setting of the study, because our patients were recruited from geriatrics and internal medicine departments, and only a few were from neurology departments. Neurologists may be more prone to prescription of antithrombotic therapy for stroke prevention. Moreover, most of the important trials supporting the efficacy of secondary prevention were performed in the late 1980s and early 1990s. This time lag may have been insufficient to translate by 1993 these results into routine clinical practice. In fact, we observed a significant increment in the prescription rate between 1993 and 1997; in 1998, the rate of prescription of our study (69%) was very similar to the rate reported by another Italian study in the same year (72%).20 Indeed, more recent studies published in the past 3 years reported a higher prevalence (>70%) of patients treated with antithrombotic medications for secondary prevention of stroke;21,22 nevertheless, in agreement with our data, implementation of international guidelines seems to be not yet adequate, particularly among the oldest patients.23

The most important independent correlates of no treatment with antithrombotic therapy were cognitive impairment and disability, and the association between disability and cognitive impairment increases further the probability of being untreated. Furthermore, even among patients with normal cognitive function there was a direct and graded association between physical performance status and the likelihood of being treated. The association between disability and antithrombotic prescription rate is difficult to explain, because there is no evidence of a lower effectiveness of antithrombotic therapy in patients with functional impairment. Conversely, stroke recurrence in these patients can increase the severity of disability and worsening their quality of life.

With regard to cognitive status, some studies showed that increasing level of cognitive impairment has been associated with a decreased use of cardiovascular and analgesic medications.24 Our results seem to confirm these previous findings also in patients with stroke. Although, prescription of anticoagulant cannot be feasible in patients with severe cognitive impairment, our stratified analysis demonstrated that almost 40% of non-disabled patients with moderate cognitive impairment were not treated with any antithrombotic medication, and this rate was substantially higher compared with patients with normal cognitive function. From this point of view, it seems unlikely that the low rate of antithrombotic prescription in patients with cognitive decline would be explained by the impossibility to prescribe anticoagulants. Impaired cognitive function is associated with an increased incidence and recurrence of stroke.25 However, stroke, particularly recurrent stroke, is a strong risk factor for cognitive impairment and dementia.26

Some of the limitations of our survey have been already mentioned. Another limitation could be that patients who had ischemic stroke with secondary hemorrhagic complications were not identified; however, the prevalence of this condition is usually low and the results should not be affected by this misclassification. We considered peptic disease, gastroduodenitis, and adverse drug reaction onset during the hospital stay or patient refusal as potential contraindications for antithrombotic therapy, but the study protocol did not gather information on previous intolerance to antithrombotics. Finally, although we analyzed a number of demographic and clinical characteristics, other measures that were not available for this study, including level of disease severity, could have provided more precise and appropriate information.

In conclusion, although antithrombotic therapy has been consistently demonstrated as an effective tool in stroke secondary prevention, our results highlighted an unexpected low rate of antiplatelet and anticoagulant prescription. Our data suggest that secondary prevention of cerebrovascular disease should be substantially improved and underline the need for therapeutic decisions to be based on the best evidence and should be incorporated into routine clinical practice, particularly in older patients with moderate cognitive or functional impairment.

Acknowledgments

This research was conducted on behalf of the investigators of the Gruppo Italiano di Farmacoepidemiologia nell’Anziano (GIFA). A complete list of the GIFA investigators has been published previously. (Pharmacol Res. 1999;40:287–295).